Project Summary Alzheimer?s disease (AD) is the most common form of dementia affecting one in nine people over the age of 65. Brain deposits of amyloid plaques and neurofibrillary tangles, which are products of APP and tau misprocessing, respectively, characterize AD. The majority (~95%) of the AD cases are sporadic and generate amyloid plaques and tangles in the absence of mutations in the APP or tau proteins, suggesting that additional factors may be necessary. The presence of various cell cycle markers in postmortem AD brains has led a number of researchers to suggest a potential role of aberrant cell cycle in AD. Our published study demonstrated that persistent cell cycle dysregulation in postmitotic neurons produce endogenous AD-like amyloid and tau pathologies and neuronal loss in mice. However, the neuropathology in our mice did not fully resemble the features of amyloid plaques and tangles observed in human AD brains. We postulate that this is likely due to differences between mouse vs. human APP and tau proteins. In this project, we will directly examine whether combining our conditional SV40T transgenic mice with humanized APP knock-in mice and humanized tau knock-in mice will produce AD-relevant plaques and tangles in animals that normally do not show A? and tau aggregation. The outcomes of the experiments will open up new lines of investigation into the mechanisms of pathological tau and APP processing in the context of sporadic Alzheimer?s disease.